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- Dosing accuracy of two disposable insulin pens according to new ISO 11608-1: 2012 requirements. (2015)
- OBJECTIVE: The aim was to compare 2 disposable insulin pens, FlexTouch® (Novo Nordisk, insulin aspart) and SoloSTAR® (Sanofi, insulin glulisine), according to new ISO 11608-1:2012 requirements for dosing accuracy. METHODS: Sixty pens of each type were tested at 1, 40, and 80 U doses. Following the new ISO requirements, each dose was delivered from the front, middle, and rear one-third of the pen. Statistical analysis was performed using Student's t test. RESULTS: Both pens delivered all doses within ISO limits. The difference between the average measured dose and the target dose was significantly smaller for SoloSTAR than FlexTouch at 40 U (P = .009) and 80 U (P = .008), but not at 1 U (P = .417). CONCLUSION: Both insulin pens fulfilled the dosing accuracy requirements defined by ISO 11608-1:2012 at all 3 dosage levels.
- Urate transporter inhibitor lesinurad is a selective peroxisome proliferator-activated receptor gamma modulator (sPPARγM) in vitro (2018)
- Gout is the most common arthritic disease in human but was long neglected and therapeutic options are not satisfying. However, with the recent approval of the urate transporter inhibitor lesinurad, gout treatment has experienced a major innovation. Here we show that lesinurad possesses considerable modulatory potency on peroxisome proliferator-activated receptor γ (PPARγ). Since gout has a strong association with metabolic diseases such as type 2 diabetes, this side-activity appears as very valuable contributing factor to the clinical efficacy profile of lesinurad. Importantly, despite robustly activating PPARγ in vitro, lesinurad lacked adipogenic activity, which seems due to differential coactivator recruitment and is characterized as selective PPARγ modulator (sPPARγM).
- MH84 improves mitochondrial dysfunction in a mouse model of early Alzheimer’s disease (2018)
- Background: Current approved drugs for Alzheimer’s disease (AD) only attenuate symptoms, but do not cure the disease. The pirinixic acid derivate MH84 has been characterized as a dual gamma-secretase/proliferator activated receptor gamma (PPARγ) modulator in vitro. Pharmacokinetic studies in mice showed that MH84 is bioavailable after oral administration and reaches the brain. We recently demonstrated that MH84 improved mitochondrial dysfunction in a cellular model of AD. In the present study, we extended the pharmacological characterization of MH84 to 3-month-old Thy-1 AβPPSL mice (harboring the Swedish and London mutation in human amyloid precursor protein (APP)) which are characterized by enhanced AβPP processing and cerebral mitochondrial dysfunction, representing a mouse model of early AD. Methods: Three-month-old Thy-1 AβPPSL mice received 12 mg/kg b.w. MH84 by oral gavage once a day for 21 days. Mitochondrial respiration was analyzed in isolated brain mitochondria, and mitochondrial membrane potential and ATP levels were determined in dissociated brain cells. Citrate synthase (CS) activity was determined in brain tissues and MitoTracker Green fluorescence was measured in HEK293-AβPPwt and HEK293-AβPPsw cells. Soluble Aβ1–40 and Aβ1–42 levels were determined using ELISA. Western blot analysis and qRT-PCR were used to measure protein and mRNA levels, respectively. Results: MH84 reduced cerebral levels of the β-secretase-related C99 peptide and of Aβ40 levels. Mitochondrial dysfunction was ameliorated by restoring complex IV (cytochrome-c oxidase) respiration, mitochondrial membrane potential, and levels of ATP. Induction of PPARγ coactivator-1α (PGC-1α) mRNA and protein expression was identified as a possible mode of action that leads to increased mitochondrial mass as indicated by enhanced CS activity, OXPHOS levels, and MitoTracker Green fluorescence. Conclusions: MH84 modulates β-secretase processing of APP and improves mitochondrial dysfunction by a PGC-1α-dependent mechanism. Thus, MH84 seems to be a new promising therapeutic agent with approved in-vivo activity for the treatment of AD.
- Tertiary alkylamines as nucleophiles in substitution reactions at heteroaromatic halide during the synthesis of the highly potent pirinixic acid derivative 2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)octanoic acid (YS-121) (2011)
- YS-121 [2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)octanoic acid] is the result of target-oriented structural derivatization of pirinixic acid. It is a potent dual PPARα/γ-agonist, as well as a potent dual 5-LO/mPGES-1-inhibitor. Additionally, recent studies showed an anti-inflammatory efficacy in vivo. Because of its interference with many targets, YS-121 is a promising drug candidate for the treatment of inflammatory diseases. Ongoing preclinical studies will thus necessitate huge amounts of YS-121. To cope with those requirements, we have optimized the synthesis of YS-121. Surprisingly, we isolated and characterized byproducts during the resulting from nucleophilic aromatic substitution reactions by different tertiary alkylamines at a heteroaromatic halide. These amines should actually serve as assisting bases, because of their low nucleophilicity. This astonishing fact was not described in former publications concerning that type of reaction and, therefore, might be useful for further reaction improvement in general. Furthermore, we could develop a proposal for the mechanism of that byproduct formation.
- Substrate-specific effects of pirinixic acid derivatives on ABCB1-mediated drug transport (2016)
- Pirinixic acid derivatives, a new class of drug candidates for a range of diseases, interfere with targets including PPARα, PPARγ, 5-lipoxygenase (5-LO), and microsomal prostaglandin and E2 synthase-1 (mPGES1). Since 5-LO, mPGES1, PPARα, and PPARγ represent potential anti-cancer drug targets, we here investigated the effects of 39 pirinixic acid derivatives on prostate cancer (PC-3) and neuroblastoma (UKF-NB-3) cell viability and, subsequently, the effects of selected compounds on drug-resistant neuroblastoma cells. Few compounds affected cancer cell viability in low micromolar concentrations but there was no correlation between the anti-cancer effects and the effects on 5-LO, mPGES1, PPARα, or PPARγ. Most strikingly, pirinixic acid derivatives interfered with drug transport by the ATP-binding cassette (ABC) transporter ABCB1 in a drug-specific fashion. LP117, the compound that exerted the strongest effect on ABCB1, interfered in the investigated concentrations of up to 2μM with the ABCB1-mediated transport of vincristine, vinorelbine, actinomycin D, paclitaxel, and calcein-AM but not of doxorubicin, rhodamine 123, or JC-1. In silico docking studies identified differences in the interaction profiles of the investigated ABCB1 substrates with the known ABCB1 binding sites that may explain the substrate-specific effects of LP117. Thus, pirinixic acid derivatives may offer potential as drug-specific modulators of ABCB1-mediated drug transport.
- Zafirlukast is a dual modulator of human soluble epoxide hydrolase and peroxisome proliferator-activated receptor γ (2019)
- Cysteinyl leukotriene receptor 1 antagonists (CysLT1RA) are frequently used as add-on medication for the treatment of asthma. Recently, these compounds have shown protective effects in cardiovascular diseases. This prompted us to investigate their influence on soluble epoxide hydrolase (sEH) and peroxisome proliferator activated receptor (PPAR) activities, two targets known to play an important role in CVD and the metabolic syndrome. Montelukast, pranlukast and zafirlukast inhibited human sEH with IC50 values of 1.9, 14.1, and 0.8 μM, respectively. In contrast, only montelukast and zafirlukast activated PPARγ in the reporter gene assay with EC50 values of 1.17 μM (21.9% max. activation) and 2.49 μM (148% max. activation), respectively. PPARα and δ were not affected by any of the compounds. The activation of PPARγ was further investigated in 3T3-L1 adipocytes. Analysis of lipid accumulation, mRNA and protein expression of target genes as well as PPARγ phosphorylation revealed that montelukast was not able to induce adipocyte differentiation. In contrast, zafirlukast triggered moderate lipid accumulation compared to rosiglitazone and upregulated PPARγ target genes. In addition, we found that montelukast and zafirlukast display antagonistic activities concerning recruitment of the PPARγ cofactor CBP upon ligand binding suggesting that both compounds act as PPARγ modulators. In addition, zafirlukast impaired the TNFα triggered phosphorylation of PPARγ2 on serine 273. Thus, zafirlukast is a novel dual sEH/PPARγ modulator representing an excellent starting point for the further development of this compound class.
- Transepithelial transport of curcumin in caco-2 cells is significantly enhanced by micellar solubilisation (2016)
- Curcumin, the active constituent of Curcuma longa L. (family Zingiberaceae), has gained increasing interest because of its anti-cancer, anti-inflammatory, anti-diabetic, and anti-rheumatic properties associated with good tolerability and safety up to very high doses of 12 g. Nanoscaled micellar formulations on the base of Tween 80 represent a promising strategy to overcome its low oral bioavailability. We therefore aimed to investigate the uptake and transepithelial transport of native curcumin (CUR) vs. a nanoscaled micellar formulation (Sol-CUR) in a Caco-2 cell model. Sol-CUR afforded a higher flux than CUR (39.23 vs. 4.98 μg min−1 cm−2, respectively). This resulted in a higher Papp value of 2.11 × 10−6 cm/s for Sol-CUR compared to a Papp value of 0.56 × 10−6 cm/s for CUR. Accordingly a nearly 9.5 fold higher amount of curcumin was detected on the basolateral side at the end of the transport experiments after 180 min with Sol-CUR compared to CUR. The determined 3.8-fold improvement in the permeability of curcumin is in agreement with an up to 185-fold increase in the AUC of curcumin observed in humans following the oral administration of the nanoscaled micellar formulation compared to native curcumin. The present study demonstrates that the enhanced oral bioavailability of micellar curcumin formulations is likely a result of enhanced absorption into and increased transport through small intestinal epithelial cells.
- A single-dose, randomized, cross-over, two-way, open-label study for comparing the absorption of boswellic acids and its lecithin formulation (2016)
- Background: The oral administration of the gum resin extracts of Indian frankincense (Boswellia serrata Roxb. ex Colebr) results in very low plasma concentrations of boswellic acids (BAs), being far below the pharmacologically active concentrations required in vitro for anti-inflammatory activity. For that reason the use of Indian frankincense in clinical practice and pharmaceutical development has substantially lagged behind. Recently the application of new formulation technologies resulted in a formulation of frankincense extract with lecithin, which revealed improved absorption and tissue penetration of BAs in a rodent study, leading for the first time to plasma concentrations of BAs in the range of their anti-inflammatory activity. Purpose: In order to verify these encouraging results in humans, the absorption of a standardized Boswellia serrata extract (BE) and its lecithin formulation (CSP) was comparatively investigated in healthy volunteers. Study design: According to a randomized cross-over design with two treatments, two sequences and two periods, 12 volunteers alternatively received the lecithin-formulated Boswellia extract (CSP) or the non-formulated Boswellia extract (BE) at a dosage of 2 × 250 mg capsules. Methods: The plasma concentrations of the six major BAs (KBA, AKBA, βBA, αBA, AβBA, AαBA) were determined using LC/MS. Results: With the exception of KBA, a significantly higher (both in terms of weight-to-weight and molar comparison) and quicker absorption of BAs from the lecithin formulation was observed, leading to Cmax in the range required for the interaction with their molecular targets. Conclusion: These findings pave the way to further studies evaluating the clinical potential of BAs, and verify the beneficial effect of lecithin formulation to improve the absorption of poorly soluble phytochemicals.
- Allosteric modulation of the farnesoid X receptor by a small molecule (2018)
- The bile acid activated transcription factor farnesoid X receptor (FXR) regulates numerous metabolic processes and is a rising target for the treatment of hepatic and metabolic disorders. FXR agonists have revealed efficacy in treating non-alcoholic steatohepatitis (NASH), diabetes and dyslipidemia. Here we characterize imatinib as first-in-class allosteric FXR modulator and report the development of an optimized descendant that markedly promotes agonist induced FXR activation in a reporter gene assay and FXR target gene expression in HepG2 cells. Differential effects of imatinib on agonist-induced bile salt export protein and small heterodimer partner expression suggest that allosteric FXR modulation could open a new avenue to gene-selective FXR modulators.
